Synthesis of 3-hydroxy-5-alkoxyhomophthalates by domino '2:1-coupling/intramolecular aldol condensation' reactions of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with tetraalkoxymethanes

Article abstract of DOI:10.1039/b918466j

The first domino '2:1 condensation/intramolecular aldol' reactions of 1,3-bis(trimethylsilyloxy)-1,3-butadiene with tetraalkoxymethanes provide a convenient approach to 3-hydroxy-5-alkoxyhomophthalates. These products, which contain one free and one protected hydroxyl group, can be functionalized by palladium(0)-catalyzed cross-coupling reactions. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b918466j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of 3-hydroxy-5-alkoxyhomophthalates by domino
‘2 : 1-coupling/intramolecular aldol condensation’ reactions of
1,3-bis(trimethylsilyloxy)-1,3-butadienes with tetraalkoxymethanes†
Mathias Lubbea and Peter Langer*a,b
Received 8th September 2009, Accepted 20th November 2009
First published as an Advance Article on the web 18th December 2009
DOI: 10.1039/b918466j
The first domino ‘2 : 1 condensation/intramolecular aldol’ reactions of
1,3-bis(trimethylsilyloxy)-1,3-butadiene with tetraalkoxymethanes provide a convenient approach to
3-hydroxy-5-alkoxyhomophthalates. These products, which contain one free and one protected
hydroxyl group, can be functionalized by palladium(0)-catalyzed cross-coupling reactions.
trianion of heptane-2,4,6-trione with carbon dioxide. The reaction
proceeds by formation of hepta-2,4,6-triketo-1,7-dicarboxylic acid
B and subsequent cyclization.5
Introduction
A great variety of pharmacologically important natural prod-
ucts are biosynthetically derived from poly(b-oxo)carboxylic
acids (polyketides, A).1 This includes a variety of polyhydroxy-
lated arenes, which are biogenetically formed by intramolecu-
lar aldol condensation of polyketides. Naturally occurring 3-
hydroxyhomophthalic acid derivatives, such as premithramyci-
non H (C)2 and sclerin (D),3 are biogenetically derived from
triketodicarboxylic acids, such as parent hepta-2,4,6-triketo-1,7-
dicarboxylic acid B, which can be regarded as pentaketides
(Scheme 1).
1,3-Bis(silyloxy)-1,3-butadienes can be regarded as equivalents
of 1,3-dicarbonyl dianions.6 Recently, we reported the synthe-
sis of 3,5-dioxoesters by condensation of 1,3-bis(silyloxy)-1,3-
butadienes with acid chlorides.7 In addition, 3,5-dioxopimelic acid
diesters, stable 1,3,5,7-tetracarbonyl derivatives, were prepared by
reaction of 1,3-bis(silyloxy)-1,3-butadienes with methyl malonyl
chloride.8 Chan and Brownbridge have reported the synthesis
of homophthalates by 2 : 1 condensation of 1,3-bis(silyloxy)-1,3-
butadienes with trimethyl orthoformate or 1,1,1-trimethoxyethane
and subsequent cyclization by intramolecular aldol reaction.3
We have reported the synthesis of 4-methoxysalicylates by [3 +
3] cyclocondensation of 1,3-bis(silyloxy)-1,3-butadienes with 3-
oxo-orthoesters.9 Homophthalates have also been prepared by
[4 + 2] cycloaddition of 1,3-bis(silyloxy)-1,3-butadienes with
dimethyl allene-1,3-dicarboxylate.10 Herein, we report a conve-
nient approach to 3-hydroxy-5-alkoxyhomophthalates by what
are, to the best of our knowledge, the first domino ‘2 : 1-
coupling/intramolecular aldol condensation’ reactions of 1,3-
bis(silyloxy)-1,3-butadienes with tetraalkoxymethanes.
Results and discussion
The TiCl4-mediated reaction of 1-methoxy-1,3-bis(trimethyl-
silyloxy)-1,3-butadiene (2a) with tetramethoxymethane (1a)
afforded the 3-hydroxy-5-methoxyhomophthalate 3a in 67% yield
(Scheme 2). The formation of 3a can be explained by TiCl4-
mediated attack of 2a to 1a to give intermediate E, attack of a
second molecule of 2a onto E to give intermediate F, subsequent
cyclization to give intermediate G and subsequent aromatization
(before or during the aqueous work-up). The best yields were
obtained when 1a, 2a and TiCl4 were employed in a stoichiometric
ratio 1 : 2 : 2, when the reaction was carried out in a relatively
concentrated solution (5 mL of CH2Cl2 per mmol of 1a) and when
hydrochloric acid (10%) was used for the aqueous work up. The use
of other Lewis acids, such as Me3SiOTf, resulted in the formation
of complex mixtures. The yield dropped (38%) when 1a, 2a and
TiCl4 were employed in a stoichiometric ratio 1 : 2 : 1. The yield
also dropped (22%) when the reaction was carried out in a more
Scheme 1 Polyketides (A), hepta-2,4,6-triketo-1,7-dicarboxylic acid (B)
and polyketide-derived homophthalates (C, D).
Harris and coworkers reported the biomimetic synthesis of
various polyketides based on condensations of 1,3-dicarbonyl
dianions or 1,3,5-tricarbonyl trianions with carboxylic acid deriva-
tives and subsequent spontaneous intramolecular aldol reaction.4
In this context, Harris and coworkers reported the formation of
3,5-dihydroxyhomophthalic acid in low yield by reaction of the
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059,
Rostock, Germany. E-mail: peter.langer@uni-rostock.de; Fax: 00 49 381
49864112; Tel: 00 49 381 4986410
bLeibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-
Einstein-Str. 29a, 18059, Rostock, Germany
† Electronic supplementary information (ESI) available: Copies of NMR
spectra. See DOI: 10.1039/b918466j
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Table 1 Synthesis of 3a–ma
1
2
3
R1
R2
% (3)b
a
a
a
a
a
a
a
b
b
b
b
b
a
b
c
d
e
f
g
b
c
d
e
f
a
b
c
d
e
f
g
h
i
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Me
Et
nPr
iPr
iBu
(CH2)2OMe
Bn
Et
67
43
47
47
61
63
56
47
66
47
40
41
nPr
k
l
m
iPr
iBu
(CH2)2OMe
a Conditions: i, (1) 1 (1.0 equiv.), 2a (2.0 equiv.), TiCl4 (2.0 equiv.), CH2Cl2,
-78 → 20 ◦C, 14 h; (2) HCl (10%). b Yields of isolated products.
employment of two different dienes in one reaction again resulted
in the formation of complex mixtures.
Scheme 2 Possible mechanism of the formation of homophthalate 3a.
Homophthalates 3 have some synthetic utility because they
contain one free and one protected hydroxyl group. For example,
derivative 3a was transformed into its triflate 4. The Suzuki
reaction of 4 with boronic acids 5a,b afforded the biaryls 6a,b
in high yields (Scheme 3).
dilute solution (30 mL of CH2Cl2 per mmol of 1a). No product
could be isolated when the reaction was carried out at 0 ◦C instead
of -78 ◦C.
The condensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes
2a–g with tetramethoxymethane (1a) and tetraethoxymethane
(1b) afforded the 3-hydroxy-5-alkoxyhomophthalates 3a–m in 40–
67% yield (Scheme 3, Table 1). The reaction of 1a,b with dienes
containing a terminal substituent resulted in the formation of
complex mixtures. The employment of 4-alkyl-1,3-bis(silyloxy)-
1,3-butadienes resulted in the formation of complex mixtures. The
Conclusions
The reaction of 1,3-bis(trimethylsilyloxy)-1,3-butadiene with
tetraalkoxymethanes afforded 3-hydroxy-5-alkoxyhomophtha-
lates by the first domino ‘2 : 1 condensation/intramolecular aldol’
reactions. The products, which contain one free and one protected
hydroxyl group, could be functionalized by palladium(0)-catalyzed
cross-coupling reactions.
Experimental section
General comments
All solvents were dried by standard methods and all reactions
were carried out under an inert atmosphere. For 1H and 13C
NMR spectra, the deuterated solvents indicated were used. Mass
spectrometric data (MS) were obtained by electron ionization
(EI, 70 eV), chemical ionization (CI, isobutane) or electrospray
ionization (ESI). For preparative scale chromatography, silica gel
60 (0.063–0.200 mm, 70–230 mesh) was used. 1,3-Bis(silyloxy)-1,3-
butadienes 2a–g were prepared according to the literature from the
corresponding b-ketoesters in two steps.11–13
General procedure for the synthesis of 3a–m
To a CH2Cl2 solution (2 mL per mmol of 1a,b) of 1a,b (1.0 mmol)
was added 2a–g (2.0 mmol) and, subsequently, TiCl4 (0.23 mL,
2.0 mmol) at -78 ◦C. The temperature of the solution was allowed
Scheme 3 Synthesis of 6a,b. Conditions: i, Tf2O, pyridine, CH2Cl2, -78 →
20 ◦C, 4 h; ii, 5a,b, K3PO4, Pd(PPh3)4, 1,4-dioxane, reflux, 4 h.
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to warm to 20 ◦C over 12–14 h with stirring. To the solution was
added HCl (10%, 10 mL), and the organic and aqueous layer were
separated. The latter was extracted with CH2Cl2 (2 ¥ 10 mL). The
combined organic layers were dried (Na2SO4) and filtered, and
the filtrate was concentrated in vacuo. The residue was purified by
column chromatography (heptane–EtOAc = 20 : 1).
(0.23 mL, 2.0 mmol) in CH2Cl2 (5 mL), product 3d was isolated
as a colourless oil (0.146 g, 47%); Rf 0.73 (heptane–EtOAc =
1 : 1). 1H NMR (CDCl3, 250 MHz): d = 11.90 (s, 1H, OH), 6.41
4
4
(d, J = 2.7 Hz, 1H, CH), 6.26 (d, J = 2.7 Hz, 1H, CH), 5.27
3
3
(septet, J = 6.3 Hz, 1H, OCH), 4.99 (septet, J = 6.3 Hz, 1H,
3
OCH), 3.86 (s, 2H, ArCH2), 3.80 (s, 3H, OCH3), 1.36 (d, J =
6.3 Hz, 6H, CH(CH3)2), 1.23 (d, 3J = 6.3 Hz, 6H, CH(CH3)2). 13
C
Dimethyl 3-hydroxy-5-methoxy-homophthalate (3a). Starting
with 1a (0.137 g, 1.0 mmol), 2a (0.521 g, 2.0 mmol) and TiCl4
(0.23 mL, 2.0 mmol) in CH2Cl2 (5 mL), product 3a was isolated as
a colourless solid (0.170 g, 67%); mp = 77–78 ◦C; Rf 0.70 (heptane–
=
NMR (63 MHz, CDCl3): d = 170.8, 170.5 (C O), 165.6, 163.7
(C–O), 138.1 (C), 112.4 (CH), 105.7 (C), 100.1 (CH), 69.6, 68.2
(OCH), 55.3 (OCH3), 42.9 (ArCH2), 21.8, 21.7 (CH(CH3)2). IR
-1
˜
(ATR, cm ): n = 2980 (m), 2838 (m), 2878 (w), 1730 (s), 1647 (s),
1
EtOAc = 1 : 1). H NMR (CDCl3, 250 MHz): d = 11.64 (s, 1H,
1614 (s), 1577 (s), 1466 (m), 1429 (m), 1374 (s). MS (EI, 70 eV):
m/z (%) = 310 (M+, 37), 209 (42), 208 (90), 190 (14), 181 (45),
180 (100), 164 (35), 135 (15). Anal. Calcd for C16H22O6 (310.34):
C, 61.92; H, 7.15. Found: C, 61.95; H, 7.23.
4
4
OH), 6.46 (d, J = 2.7 Hz, 1H, CH), 6.29 (d, J = 2.7 Hz, 1H,
CH), 3.85–3.81 (m, 8H, 2 ¥ OCH3, ArCH2), 3.68 (s, 3H, OCH3).
13
=
C NMR (75 MHz, CDCl3): d = 171.8, 171.0 (C O), 165.7, 164.1
(C–O), 138.0 (C), 112.8 (CH), 104.9 (C), 100.1 (CH), 55.4, 51.9,
-1
˜
51.7 (OCH3), 42.7 (ArCH2). IR (ATR, cm ): n = 2952 (m), 2845
Diisobutyl 3-hydroxy-5-methoxy-homophthalate (3e). Starting
with 1a (0.137 g, 1.0 mmol), 2e (0.606 g, 2.0 mmol) and TiCl4
(0.23 mL, 2.0 mmol) in CH2Cl2 (5 mL), product 3e was isolated as
a colourless oil (0.205 g, 61%); Rf 0.72 (heptane–EtOAc = 1 : 1).
1H NMR (CDCl3, 300 MHz): d = 11.78 (s, 1H, OH), 6.42 (d, 4J =
(m), 1726 (s), 1650 (s), 1621 (s), 1585 (s), 1433 (s), 1386 (m), 1333
(s). MS (EI, 70 eV): m/z (%) = 254 (M+, 54), 223 (23), 222 (57),
195 (42), 194 (88), 190 (25), 180 (12), 179 (100), 165 (10). Anal.
Calcd for C12H14O6 (254.24): C, 56.69; H, 5.55. Found: C, 56.45;
H, 5.62.
4
3
2.6 Hz, 1H, CH), 6.29 (d, J = 2.6 Hz, 1H, CH), 4.08 (d, J =
3
7.0 Hz, 2H, OCH2), 3.91 (s, 2H, ArCH2), 3.84 (d, J = 6.6 Hz,
Diethyl 3-hydroxy-5-methoxy-homophthalate (3b). Starting
with 1a (0.137 g, 1.0 mmol), 2b (0.549 g, 2.0 mmol) and TiCl4
(0.23 mL, 2.0 mmol) in CH2Cl2 (5 mL), product 3b was isolated
as a colourless solid (0.119 g, 43%); mp = 64–65 ◦C; Rf 0.70
(heptane–EtOAc = 1 : 1). 1H NMR (CDCl3, 250 MHz): d = 11.78
(s, 1H, OH), 6.42 (d, 4J = 2.6 Hz, 1H, CH), 6.28 (d, 4J = 2.6 Hz,
1H, CH), 4.35 (q, 3J = 7.2 Hz, 2H, OCH2), 4.14 (q, 3J = 7.2 Hz,
2H, OCH2), 3.86 (s, 2H, ArCH2), 3.81 (s, 3H, OCH3), 1.36 (t, 3J =
3
2H, OCH2), 3.81 (s, 3H, OCH3), 2.06 (septet, J = 6.8 Hz, 1H,
3
CH(CH3)2), 1.90 (septet, J = 6.8 Hz, 1H, CH(CH3)2), 0.98 (d,
3J = 6.3 Hz, 6H, CH(CH3)2), 0.88 (d, 3J = 6.3 Hz, 6H, CH(CH3)2).
13
=
C NMR (75 MHz, CDCl3): d = 171.2, 171.0 (C O), 165.7, 163.9
(C–O), 138.0 (C), 112.5 (CH), 105.4 (C), 100.1 (CH), 71.8, 70.9
(OCH2), 55.4 (OCH3), 42.6 (ArCH2), 27.6, 27.5 (CH(CH3)2), 19.3,
-1
˜
19.0 (CH(CH3)2). IR (ATR, cm ): n = 2961 (s), 2875 (m), 1735
(s), 1649 (s), 1616 (s), 1577 (s), 1467 (m), 1428 (m), 1371 (s). MS
(EI, 70 eV): m/z (%) = 338 (M+, 32), 209 (38), 208 (95), 190 (12),
182 (11), 181 (45), 180 (100), 164 (20), 135 (12). HRMS (EI, 70
eV): calcd for C18H26O6 (M+) 338.17239, found 338.172288.
3
7.2 Hz, 3H, CH2CH3), 1.24 (t, J = 7.2 Hz, 3H, CH2CH3). 13C
=
NMR (75 MHz, CDCl3): d = 171.3, 170.8 (C O), 165.7, 163.9
(C–O), 138.0 (C), 112.7 (CH), 105.3 (C), 100.1 (CH), 61.4, 60.7
(OCH2), 55.3 (OCH3), 42.9 (ArCH2), 14.2, 14.0 (CH2CH3). IR
-1
˜
(ATR, cm ): n = 2985 (m), 2940 (m), 2908 (w), 1724 (s), 1641 (s),
Di(2-methoxyethyl) 3-hydroxy-5-methoxy-homophthalate (3f).
Starting with 1a (0.137 g, 1.0 mmol), 2f (0.610 g, 2.0 mmol)
and TiCl4 (0.23 mL, 2.0 mmol) in CH2Cl2 (5 mL), product 3f
was isolated as a colourless oil (0.214 g, 63%); Rf 0.23 (heptane–
1613 (s), 1588 (s), 1447 (m), 1433 (m), 1366 (s). MS (EI, 70 eV):
m/z (%) = 282 (M+, 36), 237 (22), 236 (41), 208 (29), 190 (21),
181 (41), 180 (100), 179 (21). Anal. Calcd for C14H18O6 (282.29):
C, 59.57; H, 6.43. Found: C, 59.63; H, 6.47.
1
EtOAc = 1 : 1). H NMR (CDCl3, 300 MHz): d = 11.56 (s, 1H,
4
4
OH), 6.41 (d, J = 2.6 Hz, 1H, CH), 6.29 (d, J = 2.6 Hz, 1H,
Di(n-propyl) 3-hydroxy-5-methoxy-homophthalate (3c). Start-
ing with 1a (0.137 g, 1.0 mmol), 2c (0.578 g, 2.0 mmol) and TiCl4
(0.23 mL, 2.0 mmol) in CH2Cl2 (5 mL), product 3c was isolated as
a colourless oil (0.143 g, 47%); Rf 0.74 (heptane–EtOAc = 1 : 1).
1H NMR (CDCl3, 300 MHz): d = 11.79 (s, 1H, OH), 6.42 (d, 4J =
3
3
CH), 4.42 (t, J = 4.8 Hz, 2H, OCH2), 4.23 (t, J = 4.6 Hz, 2H,
3
OCH2), 3.94 (s, 2H, ArCH2), 3.80 (s, 3H, OCH3), 3.67 (t, J =
4.8 Hz, 2H, OCH2), 3.57 (t, 3J = 4.6 Hz, 2H, OCH2), 3.39 (s, 3H,
OCH3), 3.35 (s, 3H, OCH3). 13C NMR (75 MHz, CDCl3): d =
4
3
=
171.4, 170.5 (C O), 165.5, 164.0 (C–O), 138.1 (C), 112.6 (CH),
2.6 Hz, 1H, CH), 6.28 (d, J = 2.6 Hz, 1H, CH), 4.25 (t, J =
6.8 Hz, 2H, OCH2), 4.03 (t, 3J = 6.8 Hz, 2H, OCH2), 3.88 (s, 2H,
ArCH2), 3.81 (s, 3H, OCH3), 1.82–1.57 (m, 4H, 2¥CH2CH3), 0.99
105.3 (C), 100.1 (CH), 70.3, 69.8, 64.0, 63.8 (OCH2), 58.8, 58.7,
-1
˜
55.4 (OCH3), 42.4 (ArCH2). IR (ATR, cm ): n = 2932 (m), 2889
(t, 3J = 7.5 Hz, 3H, CH2CH3), 0.90 (t, 3J = 7.5 Hz, 3H, CH2CH3).
(m), 1735 (s), 1650 (s), 1616 (s), 1576 (s), 1434 (s), 1368 (m), 1324
(s). MS (EI, 70 eV): m/z (%) = 342 (M+, 22), 267 (6), 266 (20),
208 (17), 180 (24), 164 (12), 135 (10), 59 (100). Anal. Calcd for
C16H22O8 (342.34): C, 56.13; H, 6.48. Found: C, 56.33; H, 6.34.
13
=
C NMR (75 MHz, CDCl3): d = 171.3, 171.0 (C O), 165.7, 163.9
(C–O), 138.1 (C), 112.6 (CH), 105.3 (C), 100.1 (CH), 67.2, 66.4
(OCH2), 55.4 (OCH3), 42.7 (ArCH2), 21.9, 21.8 (CH2CH3), 10.5,
-1
˜
10.3 (CH2CH3). IR (ATR, cm ): n = 2967 (m), 2839 (m), 2880
Dibenzyl 3-hydroxy-5-methoxy-homophthalate (3g). Starting
with 1a (0.137 g, 1.0 mmol), 2g (0.674 g, 2.0 mmol) and TiCl4
(0.23 mL, 2.0 mmol) in CH2Cl2 (5 mL), product 3g was isolated as
a colourless solid (0.227 g, 56%); mp = 89–90 ◦C; Rf 0.48 (heptane–
(w), 1734 (s), 1649 (s), 1615 (s), 1576 (s), 1462 (m), 1430 (m), 1397
(m). MS (EI, 70 eV): m/z (%) = 310 (M+, 27), 251 (9), 252 (19),
209 (19), 208 (47), 190 (16), 181 (38), 180 (100). Anal. Calcd for
C16H22O6 (310.14): C, 61.92; H, 7.15. Found: C, 61.84; H, 7.23.
1
EtOAc = 1 : 1). H NMR (CDCl3, 300 MHz): d = 11.62 (s, 1H,
Diisopropyl 3-hydroxy-5-methoxy-homophthalate (3d). Start-
ing with 1a (0.137 g, 1.0 mmol), 2d (0.578 g, 2.0 mmol) and TiCl4
OH), 7.28–7.15 (m, 10H, 2 ¥ Ph), 6.34 (d, 4J = 2.6 Hz, 1H, CH),
4
6.19 (d, J = 2.6 Hz, 1H, CH), 5.03 (s, 2H, OCH2), 4.85 (s, 2H,
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OCH2), 3.78 (s, 2H, ArCH2CO), 3.71 (s, 3H, OCH3). 13C NMR
(m), 2838 (m), 2878 (w), 1730 (s), 1647 (s), 1614 (s), 1577 (s), 1466
(m), 1429 (m), 1374 (s). MS (EI, 70 eV): m/z (%) = 324 (M+, 35),
223 (44), 222 (94), 196 (17), 195 (34), 194 (100), 178 (28), 167 (16).
Anal. Calcd for C17H24O6 (323.37): C, 62.95; H, 7.46. Found: C,
63.03; H, 7.61.
=
(63 MHz, CDCl3): d = 170.9, 170.4 (C O), 165.8, 164.1 (C–O),
137.9, 135.8, 135.1 (C), 128.7, 128.6, 128.5, 128.4, 128.2, 112.8
(CH), 105.1 (C), 100.2 (CH), 66.8, 66.3 (OCH2), 55.4 (OCH3),
-1
˜
42.8 (ArCH2CO). IR (ATR, cm ): n = 3008 (m), 2972 (m), 2847
(w), 1729 (s), 1648 (s), 1614 (s), 1575 (s), 1449 (m), 1432 (m), 1380
(s). MS (EI, 70 eV): m/z (%) = 406 (M+, 16), 209 (10), 181 (7),
180 (100), 92 (6), 91 (100). HRMS (EI, 70 eV): calcd for C24H22O6
(M+) 406.14109, found 406.141134.
Diisobutyl 5-ethoxy-3-hydroxy-homophthalate (3l). Starting
with 1b (0.193 g, 1.0 mmol), 2e (0.606 g, 2.0 mmol) and TiCl4
(0.23 mL, 2.0 mmol) in CH2Cl2 (5 mL), product 3l was isolated as
a colourless oil (0.139 g, 40%); Rf 0.76 (heptane–EtOAc = 1 : 1).
1H NMR (CDCl3, 300 MHz): d = 11.77 (s, 1H, OH), 6.40 (d,
4J = 2.6 Hz, 1H, CH), 6.28 (d, 4J = 2.6 Hz, 1H, CH), 4.09–4.00
(m, 4H, 2¥OCH2), 3.91 (s, 2H, ArCH2), 3.83 (d, 3J = 6.8 Hz, 2H,
Diethyl 5-ethoxy-3-hydroxy-homophthalate (3h). Starting with
1b (0.193 g, 1.0 mmol), 2b (0.549 g, 2.0 mmol) and TiCl4 (0.23 mL,
2.0 mmol) in CH2Cl2 (5 mL), product 3h was isolated as a
colourless solid (0.126 g, 47%); mp = 62–63 ◦C; Rf 0.54 (heptane–
3
OCH2), 2.06 (septet, J = 6.8 Hz, 1H, CH(CH3)2), 1.87 (septet,
1
EtOAc = 1 : 1). H NMR (CDCl3, 250 MHz): d = 11.76 (s, 1H,
3J = 6.8 Hz, 1H, CH(CH3)2), 1.40 (t, 3J = 7.0 Hz, 3H, CH2CH3)
4
4
OH), 6.39 (d, J = 2.5 Hz, 1H, CH), 6.27 (d, J = 2.5 Hz, 1H,
CH), 4.34 (q, 3J = 7.1 Hz, 2H, OCH2), 4.14 (q, 3J = 7.1 Hz, 2H,
3
3
0.98 (d, J = 6.8 Hz, 6H, CH(CH3)2), 0.88 (d, J = 6.8 Hz, 6H,
CH(CH3)2). 13C NMR (75 MHz, CDCl3): d = 171.2, 171.0 (C O),
=
3
OCH2), 4.03 (q, J = 7.1 Hz, 2H, OCH2), 3.84 (s, 2H, ArCH2),
165.7, 163.9 (C–O), 138.0 (C), 112.9 (CH), 105.2 (C), 100.5 (CH),
3
1.43–1.33 (m, 6H, 2 ¥ CH3), 1.24 (t, J = 7.1 Hz, 3H, CH3). 13C
71.8, 71.0, 63.7 (OCH2), 42.6 (ArCH2), 27.6, 27.6 (CH(CH3)2),
=
NMR (63 MHz, CDCl3): d = 171.4, 170.8 (C O), 165.6, 163.3 (C–
-1
˜
19.3, 19.0, 14.5 (CH3). IR (ATR, cm ): n = 2961 (s), 2875 (m),
O), 138.0 (C), 113.0 (CH), 105.1 (C), 100.5 (CH), 63.6, 61.4, 60.6
(OCH2), 42.8 (ArCH2), 14.5, 14.1, 14.0 (CH3). IR (ATR, cm-1):
1736 (s), 1650 (s), 1617 (s), 1576 (s), 1469 (m), 1422 (m), 1325
(s). MS (EI, 70 eV): m/z (%) = 352 (M+, 29), 223 (34), 222 (90),
195 (35), 194 (100), 178 (16), 167 (13). Anal. Calcd for C19H28O6
(352.42): C, 64.75; H, 8.01. Found: C, 64.40; H, 8.18.
˜
n = 2983 (m), 2938 (m), 2896 (w), 1731 (s), 1645 (s), 1614 (s), 1575
(s), 1462 (m), 1445 (m), 1368 (s). MS (EI, 70 eV): m/z (%) = 296
(M+, 38), 251 (21), 250 (40), 222 (28), 195 (28), 194 (100), 193 (25),
167 (14). Anal. Calcd for C15H20O6 (296.32): C, 60.80; H, 6.80.
Found: C, 60.53; H, 6.77.
Di(2-methoxyethyl) 5-ethoxy-3-hydroxy-homophthalate (3m).
Starting with 1b (0.193 g, 1.0 mmol), 2f (0.610 g, 2.0 mmol)
and TiCl4 (0.23 mL, 2.0 mmol) in CH2Cl2 (5 mL), product
3m was isolated as a colourless oil (0.145 g, 41%); Rf 0.36
(heptane/EtOAc = 1 : 1). 1H NMR (CDCl3, 300 MHz): d = 11.54
(s, 1H, OH), 6.38 (d, 4J = 2.6 Hz, 1H, CH), 6.28 (d, 4J = 2.6 Hz,
1H, CH), 4.42 (t, 3J = 4.8 Hz, 2H, OCH2CH2), 4.23 (t, 3J = 4.7 Hz,
2H, OCH2CH2), 4.03 (q, 3J = 7.1 Hz, 2H, OCH2CH3), 3.93 (s, 2H,
ArCH2), 3.67 (t, 3J = 4.8 Hz, 2H, OCH2CH2), 3.57 (t, 3J = 4.7 Hz,
2H, OCH2CH2), 3.39 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 1.39 (t,
3J = 7.1 Hz, 2H, OCH2CH3). 13C NMR (63 MHz, CDCl3): d =
Di(n-propyl) 5-ethoxy-3-hydroxy-homophthalate (3i). Starting
with 1b (0.193 g, 1.0 mmol), 2c (0.578 g, 2.0 mmol) and TiCl4
(0.23 mL, 2.0 mmol) in CH2Cl2 (5 mL), product 3i was isolated as
a colourless solid (0.212 g, 66%); mp = 55–56 ◦C; Rf 0.74 (heptane–
1
EtOAc = 1 : 1). H NMR (CDCl3, 300 MHz): d = 11.78 (s, 1H,
4
4
OH), 6.40 (d, J = 2.6 Hz, 1H, CH), 6.27 (d, J = 2.6 Hz, 1H,
CH), 4.25 (t, 3J = 6.8 Hz, 2H, OCH2), 4.07–4.00 (m, 4H, 2¥OCH2),
3.87 (s, 2H, ArCH2), 1.82–1.56 (m, 4H, 2¥CH2CH3), 1.40 (t, 3J =
7.0 Hz, CH2CH3), 0.99 (t, 3J = 7.5 Hz, 3H, CH2CH3), 0.90 (t, 3J =
7.5 Hz, 3H, CH2CH3). 13C NMR (75 MHz, CDCl3): d = 171.3,
=
171.4, 170.5 (C O), 165.5, 163.4 (C–O), 138.0 (C), 113.1 (CH),
105.1 (C), 100.5 (CH), 70.3, 69.8, 63.9, 63.8, 63.7 (OCH2), 58.8,
=
171.0 (C O), 165.7, 163.3 (C–O), 138.0 (C), 113.0 (CH), 105.1
-1
˜
58.7 (OCH3), 42.5 (ArCH2), 14.5 (CH2CH3). IR (ATR, cm ): n =
(C), 100.5 (CH), 67.1, 66.4, 63.7 (OCH2), 42.7 (ArCH2), 21.9, 21.8
2981 (m), 2931 (m), 2886 (m), 2820 (m), 1736 (s), 1650 (s), 1616
(s), 1575 (s), 1449 (s), 1370 (m), 1323 (s). MS (EI, 70 eV): m/z
(%) = 356 (M+, 29), 280 (21), 222 (22), 294 (33), 178 (11), 150 (4),
121 (8), 59 (100). Anal. Calcd for C17H24O8 (356.37): C, 57.30; H,
6.79. Found: C, 57.24; H, 6.70.
-1
˜
(CH2CH3), 14.5, 10.5, 10.3 (CH2CH3). IR (ATR, cm ): n = 2967
(m), 2838 (m), 2876 (w), 1730 (s), 1651 (s), 1615 (s), 1576 (s), 1459
(m), 1433 (m), 1406 (m). MS (EI, 70 eV): m/z (%) = 324 (M+, 23),
265 (8), 264 (16), 223 (16), 222 (47), 195 (29), 194 (100), 167 (12).
Anal. Calcd for C17H24O6 (324.37): C, 62.95; H, 7.46. Found: C,
62.70; H, 7.53.
Dimethyl 5-methoxy-3-trifluormethansulfonyloxy-homophtha-
late (4). To a stirred dichloromethane solution (30 mL) of 3a
(0.763 g, 3.0 mmol) was added pyridine (0.475 g, 6.0 mmol)
at -78 ◦C and after stirring for 10 min was dropwise added
trifluoromethanesulfonic acid anhydride (1.016 g, 3.6 mmol) at the
same temperature. The temperature of the mixture was allowed to
warm to 0 ◦C and then stirred for additional 4 h. After direct
purification by column chromatography (CH2Cl2), product 4 was
isolated as a colourless solid (1.086 g, 94%); Rf 0.44 (CH2Cl2). 1H
NMR (CDCl3, 300 MHz): d = 6.83 (d, 4J = 2.4 Hz, 1H, CH), 6.75
(d, 4J = 2.7 Hz, 1H, CH), 3.89–3.88 (m, 5H, OCH3, ArCH2), 3.85
(s, 3H, OCH3), 3.68 (s, 3H, OCH3). 13C NMR (63 MHz, CDCl3):
Diisopropyl 5-ethoxy-3-hydroxy-homophthalate (3k). Starting
with 1b (0.193 g, 1.0 mmol), 2d (0.578 g, 2.0 mmol) and TiCl4
(0.23 mL, 2.0 mmol) in CH2Cl2 (5 mL), product 3k was isolated as
a colourless oil (0.151 g, 47%); Rf 0.74 (heptane–EtOAc = 1 : 1).
1H NMR (CDCl3, 250 MHz): d = 11.89 (s, 1H, OH), 6.38 (d, 4J =
4
2.6 Hz, 1H, CH), 6.25 (d, J = 2.6 Hz, 1H, CH), 5.27 (septet,
3
3J = 6.3 Hz, 1H, OCH), 4.99 (septet, J = 6.3 Hz, 1H, OCH),
4.03 (q, 3J = 7.0 Hz, OCH2), 3.85 (s, 2H, ArCH2), 1.42–1.34 (m,
3J = 6.3 Hz, 3J = 7.0 Hz, 9H, CH2CH3, CH(CH3)2), 1.22 (d, 3J =
6.3 Hz, 6H, CH(CH3)2). 13C NMR (63 MHz, CDCl3): d = 170.8,
=
170.5 (C O), 165.6, 163.1 (C–O), 138.1 (C), 112.8 (CH), 105.5
=
(C), 100.4 (CH), 69.6, 68.2 (OCH), 63.6 (OCH2), 42.9 (ArCH2),
d = 170.6, 164.7 (C O), 161.7 (C–O), 148.9, 138.0 (C), 118.5 (q,
-1
˜
21.8, 21.7 (CH(CH3)2), 14.5 (CH2CH3). IR (ATR, cm ): n = 2980
JC,F = 320 Hz, CF3), 118.4 (C), 117.1, 107.3 (CH), 55.9, 52.4, 52.1
884 | Org. Biomol. Chem., 2010, 8, 881–885
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(OCH3), 39.8 (ArCH2). 19F NMR (CDCl3, 235 MHz): d = -73.6
114.3 (CH), 55.4, 52.0, 51.7 (OCH3), 39.4 (ArCH2), 21.1 (ArCH3).
-1
˜
(CF3).
IR (ATR, cm ): n = 2948 (m), 2847 (m), 1731 (s), 1708 (s), 1599
(s), 1574 (m), 1430 (s), 1314 (m), 1283 (s). MS (EI, 70 eV): m/z
(%) = 328 (M+, 53), 297 (28), 296 (20), 269 (59), 268 (93), 254 (19),
253 (100). Anal. Calcd for C19H20O5 (328.36): C, 69.50; H, 6.14.
Found: C, 69.53; H, 6.21.
General procedure for the synthesis of 6a,b
A 1,4-dioxane solution (2.5 mL per mmol of 4) of aryl boronic
acid 5a,b (1.3 mmol), K3PO4 (1.6 mmol)◦, Pd(PPh3)4 (3 mol%) and
triflate 4 (1.0 mmol) was stirred at 110 C for 4 h. After cooling
to 20 ◦C, a saturated aqueous solution of NH4Cl was added.
The organic and aqueous layer were separated and the latter was
extracted with diethyl ether. The combined organic layers were
dried (Na2SO4), filtered and the filtrate concentrated in vacuo.
The residue was purified by column chromatography (heptane–
EtOAc = 10 : 1).
Acknowledgements
Financial support by the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
Notes and references
Dimethyl 5-methoxy-3-phenyl-homophthalate (6a). Starting
with 4 (0.387 g, 1.0 mmol), 5a (0.159 g, 1.3 mmol), K3PO4 (0.340 g,
1.6 mmol) and Pd(PPh3)4 (0.035 g, 0.03 mmol) in 1,4-dioxane
(2.5 mL), product 6a was isolated as a light-yellow solid (0.308 g,
98%); mp = 71–72 ◦C; Rf 0.58 (heptane–EtOAc = 1 : 1). 1H NMR
(CDCl3, 300 MHz): d = 7.42–7.30 (m, 5H, Ph), 6.83 (br s, 2H,
2¥CH), 3.85–3.81 (m, 5H, OCH3, ArCH2), 3.69 (s, 3H, OCH3),
3.47 (s, 3H, OCH3). 13C NMR (75 MHz, CDCl3): d = 171.3, 169.6
1 (a) J. Staunton and K. J. Weissman, Nat. Prod. Rep., 2001, 18, 380;
(b) A. M. P. Koskinen and K. Karisalmi, Chem. Soc. Rev., 2005, 34,
677.
2 K. Krohn and J. Vitz, Eur. J. Org. Chem., 2004, 209.
3 T.-H. Chan and P. Brownbridge, J. Chem. Soc., Chem. Commun., 1981,
20.
4 For a review, see: (a) T. M. Harris and C. M. Harris, Tetrahedron, 1977,
33, 2159; see also: (b) T. P. Murray and T. M. Harris, J. Am. Chem. Soc.,
1972, 94, 8253; (c) C. M. Harris, J. S. Roberson and T. M. Harris, J. Am.
Chem. Soc., 1976, 98, 5380; (d) T. M. Harris and J. V. Hay, J. Am. Chem.
Soc., 1977, 99, 1631; (e) J. S. Hubbard and T. M. Harris, Tetrahedron
Lett., 1978, 19, 4601; (f) R. M. Sandifer, A. K. Bhattacharya and T. M.
Harris, J. Org. Chem., 1981, 46, 2260; (g) S. G. Gilbreath, C. M. Harris
and T. M. Harris, J. Am. Chem. Soc., 1988, 110, 6172.
5 T. M. Harris, P. M. Murphy and A. J. Poje, J. Am. Chem. Soc., 1976,
98, 7733.
=
(C O), 160.1 (C–O), 143.5, 141.7, 134.7 (C), 128.2, 128.0, 127.4
(CH), 125.2 (C), 115.6, 114.3 (CH), 55.4, 51.9, 51.7 (OCH3), 42.7
-1
˜
(ArCH2). IR (ATR, cm ): n = 2947 (m), 2848 (m), 1731 (s), 1709
(s), 1602 (s), 1574 (m), 1433 (s), 1313 (m), 1286 (s). MS (EI, 70
eV): m/z (%) = 314 (M+, 40), 283 (28), 282 (28), 255 (58), 254 (93),
240 (17), 239 (100). Anal. Calcd for C18H18O5 (314.33): C, 68.78;
H, 5.77. Found: C, 68.82; H, 5.72.
6 For a review of 1,3-bis(silyl enol ethers), see: P. Langer, Synthesis, 2002,
441.
7 (a) T. Rahn, V. T. H. Nguyen, T. H. T. Dang, Z. Ahmed, M. Lalk, C.
Fischer, A. Spannenberg and P. Langer, J. Org. Chem., 2007, 72, 1957;
(b) T. Rahn, T. H. T. Dang, A. Spannenberg, C. Fischer and P. Langer,
Org. Biomol. Chem., 2008, 6, 3366.
8 S. Reim, D. Michalik, K. Weisz, Z. Xiao and P. Langer, Org. Biomol.
Chem., 2008, 6, 3079.
9 M. Lubbe, J.-P. Gu¨tlein, H. Reinke and P. Langer, Synlett, 2008, 2671.
10 I. Hussain, M. A. Yawer, B. Appel, M. Sher, A. Mahal, A. Villinger
and P. Langer, Tetrahedron, 2008, 64, 8003.
11 T. H. Chan and P. Brownbridge, J. Am. Chem. Soc., 1980, 102,
3534.
Dimethyl 5-methoxy-3-(4-tolyl)-homophthalate (6b). Starting
with 4 (0.271 g, 0.70 mmol), 5b (0.124 g, 0.91 mmol), K3PO4
(0.238 g, 1.6 mmol) and Pd(PPh3)4 (0.025 g, 0.02 mmol) in 1,4-
dioxane (2.0 mL), product 6b was isolated as a light-yellow solid
(0.210 g, 92%); mp = 69–70 ◦C; Rf 0.60 (heptane–EtOAc = 1 : 1).
1H NMR (CDCl3, 300 MHz): d = 7.24–7.17 (m, 4H, 4 ¥ CH), 6.82–
6.80 (m, 2H, 2 ¥ CH), 3.84 (s, 3H, OCH3), 3.79 (s, 2H, ArCH2),
3.69 (s, 3H, OCH3), 3.51 (s, 3H, OCH3), 2.38 (s, 3H, ArCH3). 13
C
12 G. A. Molander and K. O. Cameron, J. Am. Chem. Soc., 1993, 115,
=
NMR (75 MHz, CDCl3): d = 171.3, 169.7 (C O), 160.1 (C–O),
830.
143.4, 138.3, 137.1, 134.5 (C), 128.9, 127.9 (CH), 125.3 (C), 115.4,
13 V. T. H. Nguyen, E. Bellur and B. Appel, Synthesis, 2006, 2865.
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The Royal Society of Chemistry 2010
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